1. Field of the Invention
The present invention is concerned with novel peptide compounds having LHRH antagonist activity, and with pharmaceutical compositions containing said novel peptide compounds, as well as their use in methods of reducing fertility.
2. Brief Description of the Prior Art
Luteinizing hormone-releasing hormone (LHRH) is a neurohumoral hormone produced in the hypothalamus which stimulates the secretion of the pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn produce changes resulting in the induction of ovulation. LHRH has the following structure: ##STR2##
Synthetic replicates of LHRH were readily available shortly after the primary sequence was disclosed in 1971 and, as a result, a sizable number of structural analogs of LHRH have been made and tested over the last few years. Some of these have proved to be more potent than LHRH as well as long-acting. See Rivier et al., Peptides 1976 (Proceedings of the Fourteenth European Peptide Symposium, Wepion, Belgium, Apr. 11-17, 1976), pp. 427-436. Thus, a D-amino acid has been utilized in the 6-position and/or N-methyl-Leu.sup.7 substitution has been made in order to obtain potent, long-acting LHRH agonists and antagonists.
A decapeptide analog of LH-RH containing a gamma-lactam as a conformational constraint is disclosed by R. M. Freidinger et al. of Merck & Co., Inc. in Science Vol. 210, pp. 656-8 (1980) and U.S. Pat. No. 4,377,515, hereby incorporated by reference. The analog was shown to be more active as an LH-RH agonist than the parent hormone and provides evidence for a bioactive conformation containing a Tyr.sup.5 -Gly.sup.6 -Leu.sup.7 -Arg.sup.8 beta-turn.
Analog studies have also shown that the hydrophobic or basic D-amino acids in position 6 enhance potency. See Nestor, et al. J. Med. Chem. 25, 795 (1982) and Hocart et al., "Peptides, Structure and Function", Proceedings of the Eighth American Peptide Symposium, V. Hruby and D. Rich, Ed., Pierce Chemical Co., Rockford, Ill., 1983, p. 337.
Decapeptide LHRH antagonists have been disclosed; for example, see Science, vol. 218, pp. 160-2 (1982). Also, Khim. Prir. Soedin 1983 (3), pp. 398-9 (Russ.) by Burov S. V. et al. discloses cyclo [Pro-Ser-Tyr-D-Ala-Leu-Arg] as a contraceptive agent but no data is given.
An extensive amount of work has been carried out in the somatostatin agonist area as exemplified in Nature, Vol. 292, No. 5818, pp. 55-58 (1981), D. F. Veber et al., of Merck & Co., Inc.; U.S. Pat. No. 4,140,767 to D. F. Veber; U.S. Pat. No. 4,162,248 to R. G. Strachan et al.; U.S. Pat. No. 4,235,886 to R. M. Freidinger et al.; and U.S. Pat. No. 4,310,518 to R. M. Freidinger et al. all assigned to Merck & Co., Inc.
The above references describe, inter alia, highly active cyclic hexapeptide somatostatin analogs containing a beta turn.
Due to the tremendous interest created in developing a more potent and long lasting anti-fertility agent not having the adverse side effects associated with traditional estrogen and progestogen treatment, newer LH-RH antagonist agents are constantly being investigated.